Activation of Melatonin Receptors Reduces Relapse-Like Alcohol Consumption

Abstract

Melatonin is an endogenous synchronizer of biological rhythms and a modulator of physiological functions and behaviors of all mammals. Reduced levels of melatonin and a delay of its nocturnal peak concentration have been found in alcohol-dependent patients and rats. Here we investigated whether the melatonergic system is a novel target to treat alcohol addiction. Male Wistar rats were subjected to long-term voluntary alcohol consumption with repeated abstinence phases. Circadian drinking rhythmicity and patterns were registered with high temporal resolution by a drinkometer system and analyzed by Fourier analysis. We examined potential antirelapse effect of the novel antidepressant drug agomelatine. Given that agomelatine is a potent MT1 and MT2 receptor agonist and a 5-HT2C antagonist we also tested the effects of melatonin itself and the 5-HT2C antagonist SB242084. All drugs reduced relapse-like drinking. Agomelatine and melatonin administered at the end of the light phase led to very similar changes on all measures of the post-abstinence drinking behavior, suggesting that effects of agomelatine on relapse-like behavior are mostly driven by its melatonergic activity. Both drugs caused a clear phase advance in the diurnal drinking pattern when compared with the control vehicle-treated group and a reduced frequency of approaches to alcohol bottles. Melatonin given at the onset of the light phase had no effect on the circadian phase and very small effects on alcohol consumption. We conclude that targeting the melatonergic system in alcohol-dependent individuals can induce a circadian phase advance, which may restore normal sleep architecture and reduce relapse behavior.

Circadian Modulation of Alcohol-Induced Sedation and Recovery in Male and Female Drosophila

“…Recent research using rodent models has shown that inhibition of Casein-Kinase-1 –epsilon/delta, a key component of the circadian oscillator, decreases relapse drinking after alcohol withdrawal (Perreau-Lenz et al, 2012). Similarly, phase-specific treatment with melatonin or the melatonin receptor agonist agomelatine also reduces relapse-like alcohol consumption after withdrawal in rats (Vengeliene et al, 2015). Given the impact of the circadian clock with alcohol consumption and alcohol toxicity and the bidirectional impact of alcohol use on circadian rhythms, there is a continuing need to understand the mechanisms of these interactions.…”

Melatonin decreases cocaine-induced locomotor activity in pinealectomized rats

“…Several studies have reported that, in rats and mice, the behavioral effects of cocaine, 6,7 nicotine, 8 and alcohol 30 depend on the time of day of administration. 6,38 These studies have found a strong behavioral sensitization response to cocaine in the early morning, during the light phase (ZT4), and a decrease at the end of the light phase (ZT12), reaching its lowest levels at the end of the dark phase (ZT20).…”

“…24,25 It was recently reported elsewhere that melatonin decreased cocaine self-administration in rats 26 and modulated alcohol-seeking and decreased alcohol relapse-like behaviors in rats. 30 Luzindole blocked melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats Several studies have described the effect of luzindole (an MT 1 and MT 2 melatonin receptor antagonist) on melatonin-induced behavior. 49 Han et al 49 reported that systemic or intracerebral administration of 25 or 50 mg/kg melatonin to KM mice prevented the expression of morphine-induced CPP; this effect was reversed by treatment with luzindole.…”

“…10 No such diurnal variation is found in C57BL/6J mice, which are considered melatonin-deficient due to disruption of an arylalkylamine N-acetyltransferase gene (the rate-limiting enzyme in melatonin synthesis). 11 Given the large body of evidence suggesting that melatonin regulates diurnal cocaine-induced variations 10,11,29 and decreases the reinforcing effects of nicotine 27 and alcohol 30 in mice, this study sought to explore the effect of melatonin administration at different times of day (ZT4, ZT10, ZT16, and ZT22) on cocaine-induced locomotor activity in naïve and pinealectomized rats. We hypothesized that melatonin administration would decrease such activity.…”

Sleep Disturbances in Alcoholic Disease. Diagnpstics and Therapy

“…В крупных попу-ляционных исследованиях выявлено, что наличие инсом-нии повышает риск алкогольной зависимости в 2,4 раза [5]. С другой стороны, прием алкоголя нарушает циркадные ритмы и выработку мелатонина как у здоровых лиц, так и у пациентов с алкогольной зависимостью [32]. Выра жен-ность нарушений сна имеет прямую корреляцию со степе-нью тяжести злоупотребления алкоголем, оцененной при помощи шкалы АУДИТ.…”